A lot of medicaments contained in pharmaceutical products induce an unpleasant taste such as bitter taste, astringent taste and pungent taste when the pharmaceutical product is orally administered. In case that a medicament has such an unpleasant taste, it is very difficult for a patient to take a pharmaceutical product containing the medicament. A big problem to be solved for the preparation thereof is how to mask such an unpleasant taste of the medicament in the preparation. In order to solve this problem, i.e. in order to mask the unpleasant taste of the medicament when the medicament is orally administered, a sweetener or a flavor has hitherto usually been used as an additive, but sometimes an increased amount of the sweetener is required to fully mask a bitter taste. Alternatively, a coating of a medicament or a medicament-containing granule, and so on has been applied with a water-insoluble polymer base such as ethyl cellulose. With respect to this method, however, in order to more effectively depress an unpleasant taste of the medicament, it is necessary to coat it in more coating amount. As a result, the coating may affect a releasing amount of the medicament transferred into gastrointestinal tract and the desired release of the medicament can not be obtained, which is another problem.
For example, in case of an intrabuccally rapidly disintegrating tablet, it has been desired to produce a tablet having good disintegrability in buccal cavity and good dissolubility in gastrointestinal tract. However, when the intrabuccally rapidly disintegrating tablet contains a medicament having an unpleasant taste, it is difficult to simultaneously satisfy above the two conditions of rapid disintegrability in buccal cavity and alleviation of an unpleasant taste in buccal cavity because these conditions are inconsistent to each other, and it is furthermore difficult to simultaneously satisfy the condition of alleviating an unpleasant taste in buccal cavity and the condition of good dissolubility in gastrointestinal tract, because these conditions are also inconsistent to each other. Furthermore, it is also difficult to simultaneously satisfy all these conditions mentioned above.
The present inventors have studied for obtaining the desired preparation, and during which they have given in attention to previously granulate the medicament with the other ingredients and further to use a water-soluble polymer in the granulating procedure. It is already known that a particle (or granule) obtained by granulating a medicament is formulated into a drug preparation, for example, WO 2002/002083 discloses “a quick disintegrating tablet in buccal cavity, said quick disintegrating tablet comprising: spray-dried drug-containing particles, wherein each particle comprises a bitter tasting drug and/or a drug of inferior fluidity and a pharmaceutical preparation carrier, wherein each particle has a mean diameter of approximately 50 μm to approximately 250 μm and an apparent specific gravity of approximately 0.5 to approximately 1.2, and a saccharide.” The pharmaceutical preparation carrier in this reference includes water-insoluble polymers, gastrosoluble polymers, enterosoluble polymers, wax-like substances and saccharides as an example, in detail, the reference discloses a working example using a water-insoluble polymer. Thus it is disclosed in the patent gazette that such “a particle-form containing a medicament” which includes a water-insoluble polymer such as ethyl-cellulose may make a bitter thereof masked. In addition, it is disclosed in the patent gazette as “the fluidity of a drug that is not bitter tasting can be improved by the present invention, and in this case, the above-mentioned polymer substances, such as water-insoluble polymer, gastrosoluble polymer, enterosoluble polymer, etc., and wax-like substances, etc., a water soluble polymer, saccharide, etc., can be used as the above-mentioned carrier. Examples of the water-soluble polymers as the carrier are hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, etc.” Thus, this publication suggests that even if a medicament-containing particle which includes the medicament with a bitter taste and a water-soluble polymer is produced, the bitter taste thereof cannot be masked.
In addition, JP-A-2001-039861 discloses, for example, “a tablet obtained by mixing (1) (a) a granule in which a medicament is included in a water-soluble polymer matrix or a wax matrix and/or (b) a granule prepared by coating a medicament-containing granule with a water-soluble polymer or a water-insoluble polymer film, with (2) an excipient, (3) adding a solvent thereto, kneading the resultant mixture, and (4) placing the kneaded mixture in a mold, and then molding the kneaded mixture to form a tablet.” In the reference, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone, polyvinyl alcohol are exemplified as a water-soluble polymer. However, the granule mentioned in patent the gazette has a feature that a medicament can be gradually released in water or in gastrointestinal tract. Accordingly, the problem of the reference is contrary to that of the present invention.
In addition, WO 2000/024379 discloses a preparation method of drug-containing spherical fine particles that are useful in the production of easily-swallowed, controlled-release preparations. In detail, it discloses that “a preparation method of drug-containing spherical fine particles having a mean particle size of 200 μm or less comprising: adding a binder solution to a mixture containing an excipient powder having the property of retaining a solvent and a drug powder, and granulating by high-speed mixing.” In the reference, celluloses such as microcrystalline cellulose, methylcellulose, carmellose sodium, carmellose calcium, and low-substituted hydroxypropyl cellulose, and various starches are exemplified as an excipient having the property of retaining a solvent. However, the patent gazette discloses neither any masking of a bitter taste of a medicament nor any combination of a medicament having an unpleasant taste, methylcellulose and mannitol as in the present invention mentioned hereinafter.
In addition, JP-A-2000-191518 discloses that “a method for preparing an intrabuccally quickly disintegrating tablet, which comprises dissolving a difficultly soluble pharmaceutical agent together with a surfactant and/or a water-soluble polymer in an organic solvent or an water-containing organic solvent, coating an excipient with the solution or granulating the excipient with the solution to obtain molded products, mixing a saccharide with them, adding an organic solvent, water or an water-containing organic solvent thereto, followed by kneading, and subjecting it to a compression-molding.” However, the patent gazette discloses the improvement of dissolubility of a difficultly soluble medicament, but does not disclose a masking of a bitter taste. Additionally, the example section discloses examples only using surfactants, but does not disclose any example using a water-soluble polymer. Furthermore, the patent gazette does not disclose anything about a combination of a medicament with an unpleasant taste, methylcellulose and mannitol as the present invention discloses.